tbuckley/cabot-search huggingface dataset:
The use of RNA-based treatments in the field of cancer immunotherapy
Authors: Mohammad Chehelgerdi, Matin Chehelgerdi
Journal: Molecular Cancer (2023)

Abstract Over the past several decades, mRNA vaccines have evolved from a theoretical concept to a clinical reality. These vaccines offer several advantages over traditional vaccine techniques, including their high potency, rapid development, low-cost manufacturing, and safe administration. However, until recently, concerns over the instability and inefficient distribution of mRNA in vivo have limited their utility. Fortunately, recent technological advancements have mostly resolved these concerns, resulting in the development of numerous mRNA vaccination platforms for infectious diseases and various types of cancer. These platforms have shown promising outcomes in both animal models and humans. This study highlights the potential of mRNA vaccines as a promising alternative approach to conventional vaccine techniques and cancer treatment. This review article aims to provide a thorough and detailed examination of mRNA vaccines, including their mechanisms of action and potential applications in cancer immunotherapy. Additionally, the article will analyze the current state of mRNA vaccine technology and highlight future directions for the development and implementation of this promising vaccine platform as a mainstream therapeutic option. The review will also discuss potential challenges and limitations of mRNA vaccines, such as their stability and in vivo distribution, and suggest ways to overcome these issues. By providing a comprehensive overview and critical analysis of mRNA vaccines, this review aims to contribute to the advancement of this innovative approach to cancer treatment.
Mutation-Attention (MuAt): deep representation learning of somatic mutations for tumour typing and subtyping
Authors: Prima Sanjaya, Katri Maljanen, Riku Katainen, Sebastian M. Waszak, J. C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C. R. Boustred, H. Brittain, M. A. Brown, M. J. Caulfield, G. C. Chan, A. Giess, J. N. Griffin, A. Hamblin, S. Henderson, T. J. P. Hubbard, R. Jackson, L. J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, A. Lakey, S. E. A. Leigh, I. U. S. Leong, F. J. Leong, F. Maleady-Crowe, M. McEntagart, F. Minneci, J. Mitchell, L. Moutsianas, M. Mueller, N. Murugaesu, A. C. Need, P. O’Donovan, C. A. Odhams, C. Patch, D. Perez-Gil, M. B. Perez-Gil, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R. H. Scott, A. Siddiq, A. Siddiq, S. C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, A. L. Taylor Tavares, E. R. A. Thomas, S. R. Thompson, A. Tucci, M. J. Welland, E. Williams, K. Witkowska, S. M. Wood, M. Zarowiecki, Lauri A. Aaltonen, Oliver Stegle, Jan O. Korbel, Esa Pitkänen
Journal: Genome Medicine (2023)

Abstract Background Cancer genome sequencing enables accurate classification of tumours and tumour subtypes. However, prediction performance is still limited using exome-only sequencing and for tumour types with low somatic mutation burden such as many paediatric tumours. Moreover, the ability to leverage deep representation learning in discovery of tumour entities remains unknown. Methods We introduce here Mutation-Attention (MuAt), a deep neural network to learn representations of simple and complex somatic alterations for prediction of tumour types and subtypes. In contrast to many previous methods, MuAt utilizes the attention mechanism on individual mutations instead of aggregated mutation counts. Results We trained MuAt models on 2587 whole cancer genomes (24 tumour types) from the Pan-Cancer Analysis of Whole Genomes (PCAWG) and 7352 cancer exomes (20 types) from the Cancer Genome Atlas (TCGA). MuAt achieved prediction accuracy of 89% for whole genomes and 64% for whole exomes, and a top-5 accuracy of 97% and 90%, respectively. MuAt models were found to be well-calibrated and perform well in three independent whole cancer genome cohorts with 10,361 tumours in total. We show MuAt to be able to learn clinically and biologically relevant tumour entities including acral melanoma, SHH-activated medulloblastoma, SPOP -associated prostate cancer, microsatellite instability, POLE proofreading deficiency, and MUTYH -associated pancreatic endocrine tumours without these tumour subtypes and subgroups being provided as training labels. Finally, scrunity of MuAt attention matrices revealed both ubiquitous and tumour-type specific patterns of simple and complex somatic mutations. Conclusions Integrated representations of somatic alterations learnt by MuAt were able to accurately identify histological tumour types and identify tumour entities, with potential to impact precision cancer medicine.
A systematic review on artifact removal and classification techniques for enhanced MEG-based BCI systems
Authors: Beril Susan Philip, Girijesh Prasad, D Jude Hemanth
Journal: Brain-Computer Interfaces (2023)

Neurological disease victims may be completely paralyzed and unable to move, but they may still be able to think. Their brain activity is the only means by which they can interact with their environment. Brain-Computer Interface (BCI) research attempts to create tools that support subjects with disabilities. Furthermore, BCI research has expanded rapidly over the past few decades as a result of the interest in creating a new kind of human-to-machine communication. As magnetoencephalography (MEG) has superior spatial and temporal resolution than other approaches, it is being utilized to measure brain activity non-invasively. The recorded signal includes signals related to brain activity as well as noise and artifacts from numerous sources. MEG can have a low signal-to-noise ratio because the magnetic fields generated by cortical activity are small compared to other artifacts and noise. By using the right techniques for noise and artifact detection and removal, the signal-to-noise ratio can be increased. This article analyses various methods for removing artifacts as well as classification strategies. Additionally, this offers a study of the influence of Deep Learning models on the BCI system. Furthermore, the various challenges in collecting and analyzing MEG signals as well as possible study fields in MEG-based BCI are examined.
Ask the expert: assessment of shoulder pain in primary care
Authors: Richard J Murphy, Fiona Bintcliffe
Journal: BMJ (2023)

### What you need to know Orthopaedic specialists Richard Murphy and Fiona Bintcliffe provide expert answers to GPs’ questions on shoulder pain, including advice on assessing patients with shoulder pain, clinical tests, when investigations may be indicated, and how to manage subacromial pain syndrome. You make a diagnosis of subacromial pain syndrome in a 58 year old man who presents with non-traumatic pain in his right shoulder. The pain is localised around the acromion and is made worse by lifting his arm. He has a painful arc from 60° to 120° when abducting his arm. ### Which of the following treatments should you recommend first? 1. Weekly corticosteroid injections for six weeks 2. Referral to a physiotherapist for taping the shoulder with kinesio tape 3. Referral to a physiotherapist for an exercise programme 4. Urgent referral to secondary care because of loss of function in the arm 5. Referral for hydrodilatation. 6. (answer at end of article). ### Common conditions Patients frequently present with more than one pathology at the same time.2 When a patient presents with shoulder pain, first rule out important acute diagnoses that need urgent referral to secondary care. Red flags are listed in box 1.34 Box 1 ### Red flagsRETURN TO TEXT
Coordinated human sleeping brainwaves map peripheral body glucose homeostasis
Authors: Raphael Vallat, Vyoma D. Shah, Matthew P. Walker
Journal: Cell Reports Medicine (2023)

<h2>Summary</h2> Insufficient sleep impairs glucose regulation, increasing the risk of diabetes. However, what it is about the human sleeping brain that regulates blood sugar remains unknown. In an examination of over 600 humans, we demonstrate that the coupling of non-rapid eye movement (NREM) sleep spindles and slow oscillations the night before is associated with improved next-day peripheral glucose control. We further show that this sleep-associated glucose pathway may influence glycemic status through altered insulin sensitivity, rather than through altered pancreatic beta cell function. Moreover, we replicate these associations in an independent dataset of over 1,900 adults. Of therapeutic significance, the coupling between slow oscillations and spindles was the most significant sleep predictor of next-day fasting glucose, even more so than traditional sleep markers, relevant to the possibility of an electroencephalogram (EEG) index of hyperglycemia. Taken together, these findings describe a sleeping-brain-body framework of optimal human glucose homeostasis, offering a potential prognostic sleep signature of glycemic control.
The hidden players: Shedding light on the significance of post-translational modifications and miRNAs in Alzheimer's disease development
Authors: Ravinder Singh, Julfequar Hussain, Amandeep Kaur, Balaji Gokul Jamdare, Deepti Pathak, Kanchan Garg, Ramanpreet Kaur, Shivani Shankar, Aditya Sunkaria
Journal: Ageing Research Reviews (2023)
Novel NIR-II fluorescent probes for biliary atresia imaging
Authors: Xiaodong Zeng, Yuqin Liao, Xue Qiao, Ke Liang, Qiusi Luo, Mingbo Deng, Yishen Liu, Weijing Zhang, Xuechuan Hong, Yuling Xiao
Journal: Acta Pharmaceutica Sinica B (2023)

Biliary atresia is a rare infant disease that predisposes patients to liver transplantation and death if not treated in time. However, early diagnosis is challenging because the clinical manifestations and laboratory tests of biliary atresia overlap with other cholestatic diseases. Therefore, it is very important to develop a simple, safe and reliable method for the early diagnosis of biliary atresia. Herein, a novel NIR-II fluorescence probe, HZL2, with high quantum yield, excellent biocompatibility, low cytotoxicity and rapid excretion through the liver and gallbladder was developed based on the oil/water partition coefficient and permeability. A simple fecal sample after injection of HZL2 can be used to efficiently identify the success of the mouse model of biliary atresia for the first time, allowing for an early diagnosis of the disease. This study not only developed a simple and safe method for the early diagnosis of biliary atresia with great potential in clinical translation but also provides a research tool for the development of pathogenesis and therapeutic medicines for biliary atresia.
Clinical, biological and genome-wide comparison of carbapenem-resistant Klebsiella pneumoniae with susceptibility transformation to polymyxin B during therapy
Authors: Yuan Wang, Qixia Luo, Tao Chen, Xiaohui Chi, Yanzi Zhou, Hao Fu, Ping Lu, Luying Xiong, Tingting Xiao, Beiwen Zheng, Ping Shen, Yonghong Xiao
Journal: Clinical Microbiology and Infection (2023)

The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major clinical concern, and polymyxin B (PMB) is a 'last resort' antibiotic for its treatment. Understanding the effects of drug susceptibility transformation in CRKP-infected patients undergoing PMB treatment would be beneficial to optimize PMB treatment strategies.We retrospectively collected data from patients infected with CRKP and treated with PMB from January 2018 to December 2020. CRKPs were collected before and after PMB therapy, and patients were classified into the 'transformation' group (TG) and 'non-transformation' group (NTG) by the shift of susceptibility to PMB. We compared clinical characteristics between these groups, and further analysed the phenotypic and genome variation of CRKP after PMB susceptibility transformation.A total of 160 patients (37 in the TG and 123 in the NTG) were included in this study. The duration of PMB treatment before PMB-resistant K. pneumoniae (PRKP) appearance in TG was even longer than the whole duration of PMB treatment in NTG (8 [8] vs. 7 [6] days; p 0.0496). Compared with isogenic PMB-susceptible K. pneumoniae (PSKP), most PRKP strains had missense mutations in mgrB (12 isolates), yciC (10 isolates) and pmrB (7 isolates). The competition index of 82.4% (28/34) of PRKP/PSKP pairs was <67.6% (23/34), and 73.5% (25/34) of PRKP strains showed a higher 7-day lethality in Galleria mellonella and a greater ability to resist complement-dependent killing than their corresponding PSKP, respectively.Low dose with longer PMB treatment durations may be associated with the emergence of polymyxin resistance. The evolution of PRKP is predominantly mediated by an accumulation of mutations, including those in mgrB, yciC, and pmrB. Lastly, PRKP exhibited reduced growth and increased virulence compared with parental PSKP.
Age, host response, and mortality in COVID-19
Authors: Viviane Cordeiro Veiga, Alexandre Biasi Cavalcanti
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Increased age is a strong risk factor for mortality in patients with COVID-19. Understanding the dynamic changes in plasma biomarkers associated with age is crucial for unravelling the intricate interplay between ageing, immune response and outcomes.</b>https://bit.ly/3BWgSjP
More is better? Hypertonic saline dose and response for cystic fibrosis: efficacy, tolerability and implications for clinical practice
Authors: Scott H. Donaldson
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Higher concentrations of hypertonic saline provide greater protection against pulmonary exacerbation and respiratory symptom improvement in people with cystic fibrosis, and are generally well tolerated when delivered with rapid nebuliser systems</b>https://bit.ly/3WPkFsy
A State-of-the-Science Review of Interactions of Per- and Polyfluoroalkyl Substances (PFAS) with Renal Transporters in Health and Disease: Implications for Population Variability in PFAS Toxicokinetics
Authors: Shan Niu, Yuexin Cao, Ruiwen Chen, Megha Bedi, Alison P. Sanders, Alan Ducatman, Carla Ng
Journal: Environmental Health Perspectives (2023)

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous in the environment and have been shown to cause various adverse health impacts. In animals, sex- and species-specific differences in PFAS elimination half-lives have been linked to the activity of kidney transporters. However, PFAS molecular interactions with kidney transporters are still not fully understood. Moreover, the impact of kidney disease on PFAS elimination remains unclear.This state-of-the-science review integrated current knowledge to assess how changes in kidney function and transporter expression from health to disease could affect PFAS toxicokinetics and identified priority research gaps that should be addressed to advance knowledge.We searched for studies that measured PFAS uptake by kidney transporters, quantified transporter-level changes associated with kidney disease status, and developed PFAS pharmacokinetic models. We then used two databases to identify untested kidney transporters that have the potential for PFAS transport based on their endogenous substrates. Finally, we used an existing pharmacokinetic model for perfluorooctanoic acid (PFOA) in male rats to explore the influence of transporter expression levels, glomerular filtration rate (GFR), and serum albumin on serum half-lives.The literature search identified nine human and eight rat kidney transporters that were previously investigated for their ability to transport PFAS, as well as seven human and three rat transporters that were confirmed to transport specific PFAS. We proposed a candidate list of seven untested kidney transporters with the potential for PFAS transport. Model results indicated PFOA toxicokinetics were more influenced by changes in GFR than in transporter expression.Studies on additional transporters, particularly efflux transporters, and on more PFAS, especially current-use PFAS, are needed to better cover the role of transporters across the PFAS class. Remaining research gaps in transporter expression changes in specific kidney disease states could limit the effectiveness of risk assessment and prevent identification of vulnerable populations. https://doi.org/10.1289/EHP11885.
ATAC-ing single nucleus in idiopathic pulmonary fibrosis: TWIST1 strives back for myofibroblasts
Authors: Olivier Burgy, Arnaud A. Mailleux
Journal: European Respiratory Journal (2023)

Ageing is often associated with chronic remodelling, which is a key feature of many human diseases, including chronic respiratory diseases such as lung fibrosis. Idiopathic pulmonary fibrosis (IPF) is the most common form of pulmonary fibrosis and is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause. IPF patients have an overall median survival of 3 to 5 years, although current antifibrotics (pirfenidone and nintedanib) slow down lung function decline and may improve survival [1, 2]. The current paradigm suggests that IPF is a lung disorder of epithelial origin in which aberrant epithelial cell activation and ineffective repair lead to aberrant mesenchymal responses and accumulation, with secondary deposition of extracellular matrix (ECM) in the alveolar interstitium: one of the salient marks of fibrosis [1, 3, 4]. Fibroblasts are the main mesenchymal components responsible for tissue remodelling during normal and pathological lung tissue repair. In IPF, chronic injuries may lead to unbalanced cell–cell communication among the lung cells that would promote the persistence of activated "pathological" fibroblasts or myofibroblasts, and hence excessive and deleterious accumulation of ECM [1, 3]. Myofibroblasts have been believed for a long time now to constitute a heterogenous population with many possible cellular origins and several effector properties. Numerous studies utilising single-cell RNA sequencing (scRNA-seq) have demonstrated the existence of various mesenchymal cell lineages within the lung. These studies have also brought attention to the emergence of novel abnormal mesenchymal cell types in both IPF lung samples and preclinical mouse models of lung fibrosis [2, 5–7]. Integrated multi-omic single cell analyses in IPF lungs highlights TWIST1 as a critical transcriptional regulator for myofibroblasts <https://bit.ly/3qBjh0S>
BiTE secretion by adoptively transferred stem-like T cells improves FRα+ ovarian cancer control
Authors: A J Robert McGray, Jessie L Chiello, Takemasa Tsuji, Mark Long, Kathryn Maraszek, Nicole Gaulin, Spencer R Rosario, Suzanne M Hess, Scott I Abrams, Danuta Kozbor, Kunle Odunsi, Emese Zsiros
Journal: Journal for ImmunoTherapy of Cancer (2023)

Cancer immunotherapies can produce complete therapeutic responses, however, outcomes in ovarian cancer (OC) are modest. While adoptive T-cell transfer (ACT) has been evaluated in OC, durable effects are rare. Poor therapeutic efficacy is likely multifactorial, stemming from limited antigen recognition, insufficient tumor targeting due to a suppressive tumor microenvironment (TME), and limited intratumoral accumulation/persistence of infused T cells. Importantly, host T cells infiltrate tumors, and ACT approaches that leverage endogenous tumor-infiltrating T cells for antitumor immunity could effectively magnify therapeutic responses.Using retroviral transduction, we have generated T cells that secrete a folate receptor alpha (FRα)-directed bispecific T-cell engager (FR-B T cells), a tumor antigen commonly overexpressed in OC and other tumor types. The antitumor activity and therapeutic efficacy of FR-B T cells was assessed using FRα+ cancer cell lines, OC patient samples, and preclinical tumor models with accompanying mechanistic studies. Different cytokine stimulation of T cells (interleukin (IL)-2+IL-7 vs IL-2+IL-15) during FR-B T cell production and the resulting impact on therapeutic outcome following ACT was also assessed.FR-B T cells efficiently lysed FRα+ cell lines, targeted FRα+ OC patient tumor cells, and were found to engage and activate patient T cells present in the TME through secretion of T cell engagers. Additionally, FR-B T cell therapy was effective in an immunocompetent in vivo OC model, with response duration dependent on both endogenous T cells and FR-B T cell persistence. IL-2/IL-15 preconditioning prior to ACT produced less differentiated FR-B T cells and enhanced therapeutic efficacy, with mechanistic studies revealing preferential accumulation of TCF-1+CD39-CD69- stem-like CD8+ FR B T cells in the peritoneal cavity over solid tumors.These findings highlight the therapeutic potential of FR-B T cells in OC and suggest FR-B T cells can persist in extratumoral spaces while actively directing antitumor immunity. As the therapeutic activity of infused T cell therapies in solid tumor indications is often limited by poor intratumoral accumulation of transferred T cells, engager-secreting T cells that can effectively leverage endogenous immunity may have distinct mechanistic advantages for enhancing therapeutic responses rates.
Clinical Translation of Extracellular Vesicles
Authors: Aayushi Ghodasara, Aun Raza, Joy Wolfram, Carlos Salomon, Amirali Popat
Journal: Advanced Healthcare Materials (2023)

Extracellular vesicles (EVs) occur in a variety of bodily fluids and have gained recent attraction as natural materials due to their bioactive surfaces, internal cargo, and role in intercellular communication. EVs contain various biomolecules, including surface and cytoplasmic proteins; and nucleic acids that are often representative of the originating cells. EVs can transfer content to other cells, a process that is thought to be important for several biological processes, including immune responses, oncogenesis, and angiogenesis. An increased understanding of the underlying mechanisms of EV biogenesis, composition, and function has led to an exponential increase in preclinical and clinical assessment of EVs for biomedical applications, such as diagnostics and drug delivery. Bacterium-derived EV vaccines have been in clinical use for decades and a few EV-based diagnostic assays regulated under Clinical Laboratory Improvement Amendments have been approved for use in single laboratories. Though, EV-based products are yet to receive widespread clinical approval from national regulatory agencies such as the United States Food and Drug Administration (USFDA) and European Medicine Agency (EMA), many are in late-stage clinical trials. This perspective sheds light on the unique characteristics of EVs, highlighting current clinical trends, emerging applications, challenges and future perspectives of EVs in clinical use.
Plasma‐Derived Nanoclusters for Site‐Specific Multimodality Photo/Magnetic Thrombus Theranostics
Authors: Chia‐Hung Liu, Ming‐Che Liu, Pei‐Ru Jheng, Jiashing Yu, Yu‐Jui Fan, Jia‐Wei Liang, Yu‐Cheng Hsiao, Chih‐Wei Chiang, Nima Bolouki, Jyh‐Wei Lee, Jang‐Hsing Hsieh, Bradley W Mansel, Yan‐Ting Chen, Hieu Trung Nguyen, Er‐Yuan Chuang
Journal: Advanced Healthcare Materials (2023)

Abstract Traditional thrombolytic therapeutics for vascular blockage are affected by their limited penetration into thrombi, associated off‐target side effects, and low bioavailability, leading to insufficient thrombolytic efficacy. It is hypothesized that these limitations can be overcome by the precisely controlled and targeted delivery of thrombolytic therapeutics. A theranostic platform is developed that is biocompatible, fluorescent, magnetic, and well‐characterized, with multiple targeting modes. This multimodal theranostic system can be remotely visualized and magnetically guided toward thrombi, noninvasively irradiated by near‐infrared (NIR) phototherapies, and remotely activated by actuated magnets for additional mechanical therapy. Magnetic guidance can also improve the penetration of nanomedicines into thrombi. In a mouse model of thrombosis, the thrombosis residues are reduced by ≈80% and with no risk of side effects or of secondary embolization. This strategy not only enables the progression of thrombolysis but also accelerates the lysis rate, thereby facilitating its prospective use in time‐critical thrombolytic treatment.